SH2B adapter protein 1 (Pro-rich, PH and SH2 domain-containing signaling mediator) (PSM) (SH2 domain-containing protein 1B) (SH2-B PH domain-containing signaling mediator 1)

 SH2B1_MOUSE             Reviewed;         756 AA.
 Q91ZM2; O54867; Q05DJ7; Q792R7; Q91ZM3; Q91ZV5; Q9WVM5;
 18-MAR-2008, integrated into UniProtKB/Swiss-Prot.
 18-MAR-2008, sequence version 2.
 17-JUN-2020, entry version 139.
 RecName: Full=SH2B adapter protein 1;
 AltName: Full=Pro-rich, PH and SH2 domain-containing signaling mediator;
          Short=PSM;
 AltName: Full=SH2 domain-containing protein 1B;
 AltName: Full=SH2-B PH domain-containing signaling mediator 1;
 Name=Sh2b1; Synonyms=Sh2bpsm1;
 Mus musculus (Mouse).
 Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
 Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
 Murinae; Mus; Mus.
 NCBI_TaxID=10090;
 [1]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY, AND
 INTERACTION WITH INSR.
 PubMed=9498552; DOI=10.1093/oxfordjournals.jbchem.a021868;
 Riedel H., Wang J., Hansen H., Yousaf N.;
 "PSM, an insulin-dependent, pro-rich, PH, SH2 domain containing partner of
 the insulin receptor.";
 J. Biochem. 122:1105-1113(1997).
 [2]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 6), ALTERNATIVE SPLICING (ISOFORMS 1; 2
 AND 3), TISSUE SPECIFICITY, AND INTERACTION WITH INSR AND ISR1.
 PubMed=10594240; DOI=10.1007/s003359901183;
 Nelms K., O'Neill T.J., Li S., Hubbard S.R., Gustafson T.A., Paul W.E.;
 "Alternative splicing, gene localization, and binding of SH2-B to the
 insulin receptor kinase domain.";
 Mamm. Genome 10:1160-1167(1999).
 [3]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 4), FUNCTION, AND
 PHOSPHORYLATION.
 TISSUE=Brain;
 PubMed=11502739; DOI=10.1074/jbc.m104191200;
 Yousaf N., Deng Y., Kang Y., Riedel H.;
 "Four PSM/SH2-B alternative splice variants and their differential roles in
 mitogenesis.";
 J. Biol. Chem. 276:40940-40948(2001).
 [4]
 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
 STRAIN=NOD;
 PubMed=16141072; DOI=10.1126/science.1112014;
 Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
 Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
 Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
 Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
 Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
 Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
 Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
 Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
 Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
 Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
 Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
 Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
 Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
 Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
 Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
 Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
 Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
 Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
 Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
 Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
 Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
 Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
 Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
 Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
 Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
 van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
 Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
 Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
 Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
 Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
 Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
 Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
 Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
 Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
 "The transcriptional landscape of the mammalian genome.";
 Science 309:1559-1563(2005).
 [5]
 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 4 AND 5).
 STRAIN=C57BL/6J, and FVB/N; TISSUE=Mammary tumor;
 PubMed=15489334; DOI=10.1101/gr.2596504;
 The MGC Project Team;
 "The status, quality, and expansion of the NIH full-length cDNA project:
 the Mammalian Gene Collection (MGC).";
 Genome Res. 14:2121-2127(2004).
 [6]
 NUCLEOTIDE SEQUENCE [MRNA] OF 518-631, AND INTERACTION WITH INSR AND IGF1R.
 PubMed=9452421; DOI=10.1074/jbc.273.6.3136;
 Wang J., Riedel H.;
 "Insulin-like growth factor-I receptor and insulin receptor association
 with a Src homology-2 domain-containing putative adapter.";
 J. Biol. Chem. 273:3136-3139(1998).
 [7]
 FUNCTION IN GH SIGNALING, AND INTERACTION WITH JAK2.
 TISSUE=Kidney;
 PubMed=9343427; DOI=10.1128/mcb.17.11.6633;
 Rui L., Mathews L.S., Hotta K., Gustafson T.A., Carter-Su C.;
 "Identification of SH2-Bbeta as a substrate of the tyrosine kinase JAK2
 involved in growth hormone signaling.";
 Mol. Cell. Biol. 17:6633-6644(1997).
 [8]
 FUNCTION IN LEPTIN SIGNALING, AND INTERACTION WITH JAK2; ISR1 AND ISR2.
 PubMed=15316008; DOI=10.1074/jbc.m408495200;
 Duan C., Li M., Rui L.;
 "SH2-B promotes insulin receptor substrate 1 (IRS1)- and IRS2-mediated
 activation of the phosphatidylinositol 3-kinase pathway in response to
 leptin.";
 J. Biol. Chem. 279:43684-43691(2004).
 [9]
 FUNCTION IN LEPTIN SIGNALING.
 PubMed=16098827; DOI=10.1016/j.cmet.2005.07.004;
 Ren D., Li M., Duan C., Rui L.;
 "Identification of SH2-B as a key regulator of leptin sensitivity, energy
 balance, and body weight in mice.";
 Cell Metab. 2:95-104(2005).
 [10]
 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
 TISSUE=Liver;
 PubMed=17242355; DOI=10.1073/pnas.0609836104;
 Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
 "Large-scale phosphorylation analysis of mouse liver.";
 Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
 [11]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-88; SER-96; SER-417 AND
 SER-420, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
 TISSUE=Brain, Brown adipose tissue, Kidney, Liver, Pancreas, Spleen, and
 Testis;
 PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
 Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
 Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
 "A tissue-specific atlas of mouse protein phosphorylation and expression.";
 Cell 143:1174-1189(2010).
 [12]
 METHYLATION [LARGE SCALE ANALYSIS] AT ARG-270, AND IDENTIFICATION BY MASS
 SPECTROMETRY [LARGE SCALE ANALYSIS].
 TISSUE=Brain, and Embryo;
 PubMed=24129315; DOI=10.1074/mcp.o113.027870;
 Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M.,
 Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V.,
 Bedford M.T., Comb M.J.;
 "Immunoaffinity enrichment and mass spectrometry analysis of protein
 methylation.";
 Mol. Cell. Proteomics 13:372-387(2014).
 [13]
 X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 519-627 IN COMPLEX WITH JAK2.
 PubMed=16824542; DOI=10.1016/j.jmb.2006.05.070;
 Hu J., Hubbard S.R.;
 "Structural basis for phosphotyrosine recognition by the Src homology-2
 domains of the adapter proteins SH2-B and APS.";
 J. Mol. Biol. 361:69-79(2006).
 -!- FUNCTION: Adapter protein for several members of the tyrosine kinase
     receptor family. Involved in multiple signaling pathways mediated by
     Janus kinase (JAK) and receptor tyrosine kinases, including the
     receptors of insulin (INS), insulin-like growth factor I (IGF1), nerve
     growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial
     cell line-derived neurotrophic factor (GDNF), platelet-derived growth
     factor (PDGF) and fibroblast growth factors (FGFs). In growth hormone
     (GH) signaling, autophosphorylated ('Tyr-813') JAK2 recruits SH2B1,
     which in turn is phosphorylated by JAK2 on tyrosine residues. These
     phosphotyrosines form potential binding sites for other signaling
     proteins. GH also promotes serine/threonine phosphorylation of SH2B1
     and these phosphorylated residues may serve to recruit other proteins
     to the GHR-JAK2-SH2B1 complexes, such as RAC1. In leptin (LEP)
     signaling, binds to and potentiates the activation of JAK2 by globally
     enhancing downstream pathways. In response to leptin, binds
     simultaneously to both, JAK2 and IRS1 or IRS2, thus mediating formation
     of a complex of JAK2, SH2B1 and IRS1 or IRS2. Mediates tyrosine
     phosphorylation of IRS1 and IRS2, resulting in activation of the PI 3-
     kinase pathway. Acts as positive regulator of NGF-mediated activation
     of the Akt/Forkhead pathway; prolongs NGF-induced phosphorylation of
     AKT1 on 'Ser-473' and AKT1 enzymatic activity. Enhances the kinase
     activity of the cytokine receptor-associated tyrosine kinase JAK2 and
     of other receptor tyrosine kinases, such as FGFR3 and NTRK1. For JAK2,
     the mechanism seems to involve dimerization of both, SH2B1 and JAK2.
     Enhances RET phosphorylation and kinase activity (By similarity).
     Isoforms seem to be differentially involved in IGF-I and PDGF-induced
     mitogenesis, according the order: isoform 3 > isoform 4 > isoform 1 >
     isoform 2. {ECO:0000250, ECO:0000269|PubMed:11502739,
     ECO:0000269|PubMed:15316008, ECO:0000269|PubMed:16098827,
     ECO:0000269|PubMed:9343427}.
 -!- SUBUNIT: Self-associates. Homopentamer (By similarity). Forms a
     heteromultimeric complex with SH2B2 (By similarity). Interacts with
     SH2B2. Isoform 1 interacts via its SH2 domain with JAK2. Isoform 2
     interacts via its SH2 domain and its N-terminus with JAK2; the SH2
     domain is required for the major interaction with JAK2 phosphorylated
     on tyrosine residues; the N-terminus provides a low-affinity binding to
     JAK2 independent of JAK2 phosphorylation. Isoform 3 interacts via its
     SH2 domain with JAK2. Isoform 1 interacts via its SH2 domain with INSR;
     the interaction requires receptor activation. Isoform 3 interacts via
     its SH2 domain with INSR; the interaction requires receptor activation
     and requires INSR phosphorylation at 'Tyr-1175'. Isoform 1 interacts
     with IGF1R; the interaction requires receptor activation. Isoform 2
     interacts via its SH2 domain with FGFR3; the interaction requires FGFR3
     'Tyr-719' and 'Tyr-755'. Isoform 2 interacts with RET; the interaction
     requires RET kinase activity and RET 'Tyr-982'. Isoform 2 interacts
     with RAC1. Isoform 2 interacts with PDGFRA and/or PDGFRB; the
     interaction requires receptor activation. Interacts with ISR1 and ISR2.
     Isoform 3 is probably part of a complex consisting of INSR, ISR1 and
     SH2B1. Probably part of a ternary complex consisting of SH2B1, JAK2 and
     ISR1 or ISR2. May interact with FCER1G (By similarity). Interacts (via
     SH2 domain) with NTRK1 (phosphorylated) (By similarity). {ECO:0000250}.
 -!- INTERACTION:
     Q91ZM2; Q62120: Jak2; NbExp=3; IntAct=EBI-7178606, EBI-646604;
 -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Membrane {ECO:0000305}.
     Nucleus {ECO:0000250}. Note=Shuttles between the nucleus and the
     cytoplasm. {ECO:0000250}.
 -!- ALTERNATIVE PRODUCTS:
     Event=Alternative splicing; Named isoforms=6;
     Name=1; Synonyms=Alpha;
       IsoId=Q91ZM2-1; Sequence=Displayed;
     Name=2; Synonyms=Beta;
       IsoId=Q91ZM2-2; Sequence=VSP_032032;
     Name=3; Synonyms=Gamma;
       IsoId=Q91ZM2-3; Sequence=VSP_032033;
     Name=4; Synonyms=Delta;
       IsoId=Q91ZM2-4; Sequence=VSP_032034;
     Name=5;
       IsoId=Q91ZM2-5; Sequence=VSP_032029, VSP_032031;
     Name=6; Synonyms=Sh2bpsm1 gamma;
       IsoId=Q91ZM2-6; Sequence=VSP_032030, VSP_032033;
 -!- TISSUE SPECIFICITY: Widely expressed with highest levels in liver,
     brain and heart. Isoform 3 is widely expressed.
     {ECO:0000269|PubMed:10594240, ECO:0000269|PubMed:9498552}.
 -!- PTM: Phosphorylated on tyrosine residues in response to IGF-I and PDGF
     stimulation. {ECO:0000269|PubMed:11502739}.
 -!- SIMILARITY: Belongs to the SH2B adapter family. {ECO:0000305}.
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 EMBL; AF020526; AAC33414.1; -; mRNA.
 EMBL; AF380422; AAL07566.1; -; mRNA.
 EMBL; AF074329; AAD41655.1; -; mRNA.
 EMBL; AF421138; AAL16069.1; -; mRNA.
 EMBL; AF421139; AAL16070.1; -; mRNA.
 EMBL; AK168439; BAE40344.1; -; mRNA.
 EMBL; AK170444; BAE41802.1; -; mRNA.
 EMBL; BC011422; AAH11422.1; -; mRNA.
 EMBL; BC051978; AAH51978.1; -; mRNA.
 EMBL; AF036355; AAC39955.2; -; mRNA.
 CCDS; CCDS40126.1; -. [Q91ZM2-3]
 CCDS; CCDS85410.1; -. [Q91ZM2-4]
 CCDS; CCDS85411.1; -. [Q91ZM2-1]
 CCDS; CCDS85412.1; -. [Q91ZM2-2]
 PIR; JC5886; JC5886.
 RefSeq; NP_001074928.1; NM_001081459.2. [Q91ZM2-2]
 RefSeq; NP_001276467.1; NM_001289538.1. [Q91ZM2-1]
 RefSeq; NP_001276468.1; NM_001289539.1. [Q91ZM2-2]
 RefSeq; NP_001276469.1; NM_001289540.1. [Q91ZM2-2]
 RefSeq; NP_001276470.1; NM_001289541.1. [Q91ZM2-4]
 RefSeq; NP_001276471.1; NM_001289542.1. [Q91ZM2-4]
 RefSeq; NP_035493.2; NM_011363.3. [Q91ZM2-3]
 RefSeq; XP_006507541.1; XM_006507478.3. [Q91ZM2-1]
 RefSeq; XP_006507543.1; XM_006507480.3. [Q91ZM2-1]
 RefSeq; XP_006507544.1; XM_006507481.3. [Q91ZM2-1]
 RefSeq; XP_006507545.1; XM_006507482.1. [Q91ZM2-1]
 RefSeq; XP_006507548.1; XM_006507485.3. [Q91ZM2-3]
 RefSeq; XP_006507550.1; XM_006507487.3. [Q91ZM2-2]
 PDB; 2HDV; X-ray; 2.00 A; A/B=519-627.
 PDB; 2HDX; X-ray; 2.35 A; A/B/C/D/E/F=519-627.
 PDBsum; 2HDV; -.
 PDBsum; 2HDX; -.
 SMR; Q91ZM2; -.
 BioGRID; 203201; 2.
 IntAct; Q91ZM2; 4.
 MINT; Q91ZM2; -.
 STRING; 10090.ENSMUSP00000032978; -.
 iPTMnet; Q91ZM2; -.
 PhosphoSitePlus; Q91ZM2; -.
 jPOST; Q91ZM2; -.
 PaxDb; Q91ZM2; -.
 PeptideAtlas; Q91ZM2; -.
 PRIDE; Q91ZM2; -.
 Antibodypedia; 26583; 277 antibodies.
 Ensembl; ENSMUST00000032978; ENSMUSP00000032978; ENSMUSG00000030733. [Q91ZM2-3]
 Ensembl; ENSMUST00000205340; ENSMUSP00000145953; ENSMUSG00000030733. [Q91ZM2-2]
 Ensembl; ENSMUST00000205440; ENSMUSP00000145554; ENSMUSG00000030733. [Q91ZM2-2]
 Ensembl; ENSMUST00000205497; ENSMUSP00000145842; ENSMUSG00000030733. [Q91ZM2-4]
 Ensembl; ENSMUST00000205733; ENSMUSP00000145754; ENSMUSG00000030733. [Q91ZM2-1]
 Ensembl; ENSMUST00000205889; ENSMUSP00000146282; ENSMUSG00000030733. [Q91ZM2-4]
 Ensembl; ENSMUST00000206664; ENSMUSP00000146121; ENSMUSG00000030733. [Q91ZM2-5]
 GeneID; 20399; -.
 KEGG; mmu:20399; -.
 UCSC; uc009jrh.2; mouse. [Q91ZM2-2]
 UCSC; uc009jrj.2; mouse. [Q91ZM2-4]
 UCSC; uc009jrk.2; mouse. [Q91ZM2-3]
 UCSC; uc009jrm.2; mouse. [Q91ZM2-1]
 CTD; 25970; -.
 MGI; MGI:1201407; Sh2b1.
 eggNOG; ENOG410IMWK; Eukaryota.
 eggNOG; ENOG41102PH; LUCA.
 GeneTree; ENSGT00950000183191; -.
 HOGENOM; CLU_014885_4_0_1; -.
 InParanoid; Q91ZM2; -.
 KO; K12459; -.
 OMA; SSTLMPF; -.
 OrthoDB; 556279at2759; -.
 PhylomeDB; Q91ZM2; -.
 TreeFam; TF323184; -.
 Reactome; R-MMU-1170546; Prolactin receptor signaling.
 Reactome; R-MMU-982772; Growth hormone receptor signaling.
 Reactome; R-MMU-983231; Factors involved in megakaryocyte development and platelet production.
 BioGRID-ORCS; 20399; 4 hits in 12 CRISPR screens.
 ChiTaRS; Sh2b1; mouse.
 EvolutionaryTrace; Q91ZM2; -.
 PRO; PR:Q91ZM2; -.
 Proteomes; UP000000589; Chromosome 7.
 RNAct; Q91ZM2; protein.
 Bgee; ENSMUSG00000030733; Expressed in molar tooth and 279 other tissues.
 Genevisible; Q91ZM2; MM.
 GO; GO:0005829; C:cytosol; TAS:Reactome.
 GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
 GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
 GO; GO:0001726; C:ruffle; TAS:MGI.
 GO; GO:0005068; F:transmembrane receptor protein tyrosine kinase adaptor activity; IBA:GO_Central.
 GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
 GO; GO:0030032; P:lamellipodium assembly; IDA:MGI.
 GO; GO:0045840; P:positive regulation of mitotic nuclear division; IDA:UniProtKB.
 GO; GO:0060391; P:positive regulation of SMAD protein signal transduction; IEA:Ensembl.
 GO; GO:2000278; P:regulation of DNA biosynthetic process; IMP:UniProtKB.
 CDD; cd10346; SH2_SH2B_family; 1.
 Gene3D; 2.30.29.30; -; 1.
 Gene3D; 3.30.505.10; -; 1.
 IDEAL; IID50098; -.
 InterPro; IPR011993; PH-like_dom_sf.
 InterPro; IPR001849; PH_domain.
 InterPro; IPR015012; Phe_ZIP.
 InterPro; IPR036290; Phe_ZIP_sf.
 InterPro; IPR000980; SH2.
 InterPro; IPR036860; SH2_dom_sf.
 InterPro; IPR030523; SH2B.
 InterPro; IPR030521; SH2B1.
 InterPro; IPR035057; SH2B1_SH2.
 PANTHER; PTHR10872; PTHR10872; 1.
 PANTHER; PTHR10872:SF3; PTHR10872:SF3; 1.
 Pfam; PF00169; PH; 1.
 Pfam; PF08916; Phe_ZIP; 1.
 Pfam; PF00017; SH2; 1.
 PRINTS; PR00401; SH2DOMAIN.
 SMART; SM00233; PH; 1.
 SMART; SM00252; SH2; 1.
 SUPFAM; SSF109805; SSF109805; 1.
 SUPFAM; SSF55550; SSF55550; 1.
 PROSITE; PS50001; SH2; 1.
 1: Evidence at protein level;
 3D-structure; Alternative splicing; Cytoplasm; Membrane; Methylation;
 Nucleus; Phosphoprotein; Reference proteome; SH2 domain.
 CHAIN           1..756
                 /note="SH2B adapter protein 1"
                 /id="PRO_0000323594"
 DOMAIN          267..376
                 /note="PH"
 DOMAIN          527..625
                 /note="SH2"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
 REGION          1..555
                 /note="Interaction with JAK2 (low-affinity binding;
                 independent of JAK2 phosphorylation)"
                 /evidence="ECO:0000250"
 REGION          24..85
                 /note="Required for self-association"
                 /evidence="ECO:0000250"
 REGION          85..196
                 /note="Interaction with RAC1"
                 /evidence="ECO:0000250"
 REGION          100..243
                 /note="Required for NGF signaling"
                 /evidence="ECO:0000250"
 REGION          224..233
                 /note="Required for nuclear localization"
                 /evidence="ECO:0000250"
 MOD_RES         88
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:21183079"
 MOD_RES         96
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:21183079"
 MOD_RES         270
                 /note="Omega-N-methylarginine"
                 /evidence="ECO:0000244|PubMed:24129315"
 MOD_RES         417
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:21183079"
 MOD_RES         420
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:21183079"
 MOD_RES         439
                 /note="Phosphotyrosine; by JAK1, JAK2 and PDGFR"
                 /evidence="ECO:0000250|UniProtKB:Q62985"
 MOD_RES         494
                 /note="Phosphotyrosine; by JAK1, JAK2"
                 /evidence="ECO:0000250|UniProtKB:Q62985"
 VAR_SEQ         437..443
                 /note="GAYGGLS -> AVDSEKT (in isoform 5)"
                 /evidence="ECO:0000303|PubMed:15489334"
                 /id="VSP_032029"
 VAR_SEQ         441..460
                 /note="Missing (in isoform 6)"
                 /evidence="ECO:0000303|PubMed:10594240"
                 /id="VSP_032030"
 VAR_SEQ         444..756
                 /note="Missing (in isoform 5)"
                 /evidence="ECO:0000303|PubMed:15489334"
                 /id="VSP_032031"
 VAR_SEQ         632..756
                 /note="ERSTSRDPAQPSEPPPWTDPPHPGAEEASGAPEVAAATAAAAKERQEKEKAG
                 SGGVQEELVPVAELVPMVELEEAIAPGTEAQGGAGSSGDLEVSLMVQLQQLPLGGNGEE
                 GGHPRAINNQYSFV -> GREQAGSHAGVCEGDRCYPDASSTLLPFGASDCVTEHLP
                 (in isoform 2)"
                 /evidence="ECO:0000303|PubMed:11502739,
                 ECO:0000303|PubMed:16141072, ECO:0000303|PubMed:9498552"
                 /id="VSP_032032"
 VAR_SEQ         632..756
                 /note="ERSTSRDPAQPSEPPPWTDPPHPGAEEASGAPEVAAATAAAAKERQEKEKAG
                 SGGVQEELVPVAELVPMVELEEAIAPGTEAQGGAGSSGDLEVSLMVQLQQLPLGGNGEE
                 GGHPRAINNQYSFV -> GEQSRSAGEEVPVHPRSEAGSRLGAMQGCARATDATPMPPP
                 PSCPSERVTV (in isoform 3 and isoform 6)"
                 /evidence="ECO:0000303|PubMed:10594240,
                 ECO:0000303|PubMed:11502739, ECO:0000303|PubMed:16141072"
                 /id="VSP_032033"
 VAR_SEQ         632..756
                 /note="ERSTSRDPAQPSEPPPWTDPPHPGAEEASGAPEVAAATAAAAKERQEKEKAG
                 SGGVQEELVPVAELVPMVELEEAIAPGTEAQGGAGSSGDLEVSLMVQLQQLPLGGNGEE
                 GGHPRAINNQYSFV -> GEQSRSAGEEVPVHPRSENGAPPVTQPSPLNPLHGQIPHIL
                 GQKRRRGRQKLRQPQPQQPKRGKRKRKRAVEGSRKSWSPWLSWSPWLNWKRP (in
                 isoform 4)"
                 /evidence="ECO:0000303|PubMed:11502739,
                 ECO:0000303|PubMed:15489334"
                 /id="VSP_032034"
 CONFLICT        172
                 /note="W -> C (in Ref. 2; AAD41655)"
                 /evidence="ECO:0000305"
 CONFLICT        399
                 /note="F -> L (in Ref. 5; AAH11422)"
                 /evidence="ECO:0000305"
 CONFLICT        564
                 /note="Y -> C (in Ref. 2; AAD41655)"
                 /evidence="ECO:0000305"
 HELIX           522..524
                 /evidence="ECO:0000244|PDB:2HDV"
 STRAND          528..531
                 /evidence="ECO:0000244|PDB:2HDV"
 HELIX           534..542
                 /evidence="ECO:0000244|PDB:2HDV"
 HELIX           545..548
                 /evidence="ECO:0000244|PDB:2HDV"
 STRAND          551..556
                 /evidence="ECO:0000244|PDB:2HDV"
 STRAND          558..560
                 /evidence="ECO:0000244|PDB:2HDX"
 STRAND          563..570
                 /evidence="ECO:0000244|PDB:2HDV"
 STRAND          573..581
                 /evidence="ECO:0000244|PDB:2HDV"
 STRAND          587..589
                 /evidence="ECO:0000244|PDB:2HDV"
 STRAND          592..596
                 /evidence="ECO:0000244|PDB:2HDV"
 HELIX           597..604
                 /evidence="ECO:0000244|PDB:2HDV"
 TURN            612..616
                 /evidence="ECO:0000244|PDB:2HDX"
 SEQUENCE   756 AA;  79625 MW;  388BDC44267E6DE8 CRC64;
 MNGAPSPEDG VFPSPPALPP PPPPSWQEFC ESHARAAALD LARRFRLYLA SHPQYAEPGA
 EAAFSGRFAE LFLQHFEAEV ARASGSLSPP VLAPLSPGVE IPPSHDLSLE SCRVGGPLAV
 LGPSRSSEDL AGPLPSSVPS STTSSKPKLK KRFSLRSVGR SVRGSVRGIL QWRGAVDSPS
 QAGPLETTSG PPVLGGNSNS NSSGGAGTVG RALANDGTSP GERWTHRFER LRLSRGGGTL
 KDGAGMIQRE ELLSFMGAEE AAPDPAGVGR GGGAAGLTSG GGGQPQWQKC RLLLRSEGEG
 GGGSRLEFFV PPKASRPRLS IPCSTITDVR TATALEMPDR ENTFVVKVEG PSEYILETSD
 ALHVKAWVSD IQECLSPGPC PAISPRPMTL PLAPGTSFFT KDNTDSLELP CLNHSESLPS
 QDLLLGPSES NDRLSQGAYG GLSDRPSASF SPSSASIAAS HFDSMELLPP ELPPRIPIEE
 GPPAGTVHPL STPYPPLDTP EAATGSFLFQ GESEGGEGDQ PLSGYPWFHG MLSRLKAAQL
 VLEGGTGSHG VFLVRQSETR RGEYVLTFNF QGKAKHLRLS LNEEGQCRVQ HLWFQSIFDM
 LEHFRVHPIP LESGGSSDVV LVSYVPSQRQ QERSTSRDPA QPSEPPPWTD PPHPGAEEAS
 GAPEVAAATA AAAKERQEKE KAGSGGVQEE LVPVAELVPM VELEEAIAPG TEAQGGAGSS
 GDLEVSLMVQ LQQLPLGGNG EEGGHPRAIN NQYSFV

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